The long-term goals of the proposed research are to elucidate the ubiquitin-signaling networks that regulate neuronal connectivity and synaptic plasticity in the brain. We recently discovered that forebrain-specific conditional knockout of Cdh1, the key coactivator of the major E3 ubiquitin ligase Cdh1-APC, profoundly impairs metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) at CA1 synapses in the mouse hippocampus. In mechanistic studies, we have identified the fragile X syndrome protein FMRP as a novel substrate of Cdh1-APC in the regulation of mGluR-LTD in the hippocampus. Endogenous Cdh1-APC forms a complex with endogenous FMRP in the hippocampus, and forebrain-specific conditional knockout of Cdh1 impairs mGluR-induced ubiquitination and degradation of FMRP in the hippocampus. In epistatic analyses, knockout of FMRP suppresses the conditional Cdh1 knockout-induced mGluR-LTD phenotype. These findings define the major E3 ubiquitin ligase Cdh1-APC and fragile X syndrome protein FMRP as components of a novel ubiquitin-signaling pathway that regulates mGluR-dependent synaptic plasticity. These findings also raise fundamental questions on the mechanisms and biological implications of Cdh1-APC signaling in synaptic plasticity and disease. To address these questions, in structure-function analyses we will identify distinct domains and motifs within Cdh1 that regulate the ability of Cdh1-APC to drive mGluR-LTD in the hippocampus. We will also determine the role of Cdh1 phosphorylation and Cdh1-interacting proteins in Cdh1-APC function in mGluR-LTD. Using candidate and innovative unbiased genomics approaches, we will determine the mechanism by which Cdh1-APC/FMRP drives mGluR-LTD in the hippocampus. Finally, we will assess the biological role of Cdh1-APC signaling in a premutation model of fragile X syndrome. The proposed research represents an important set of experiments that will advance our understanding of the mechanisms that control synaptic plasticity in the brain as well as neurodevelopmental disorders of cognition.